We propose to study two specific components of our innate immune system to assess their role in host defense to Leishmania. The two components of host defense that we will study are the complement system and the epidermal Langerhans cells. These two components are involved very early in the initiation of Leishmania infection and consequently are in a unique position to impact on disease progression or resolution. We hypothesize that innate immunity can influence the development and maturation of acquired immunity. The role of complement in host defense to Leishmania will be studied in C3 minus/- mice. We have previously demonstrated that in vitro Leishmania can exploit complement to enter macrophages where they replicate. In the present proposal we will examine disease progression in animals lacking complement component C3. The opsonic, chemotactic, and lytic effects of complement will be studied in both cutaneous and visceral disease models. Parasite burdens, lesion progression, granuloma formation, and cytokine production will be analyzed. In the second aim, the recognition of Leishmania by Langerhans cells will be studied. The LC receptors involved in Leishmania promastigote adhesion and the ligand(s) on the surface of Leishmania promastigotes that are recognized by LC will be examined. Antigen presentation by LC and the potential role of Leishmania LPG as an antigen presented by CD-1 will also be examined. Leishmania infection in CD-1 knockout mice will be measured. The proposed studies involving complement and Langerhans cells relate not only to the initiation of Leishmania infection, but should also yield important new information about how our innate immune system can contribute to host defense against intracellular pathogens, in general.